Medicine and Health Sciences Commons^™

Implementation Outcomes From The Hypertension Treatment In Nigeria Program: Results From A Type 2 Hybrid Interrupted Time Series Trial, Jiancheng Ye, Erica L Jamro, Guhan Iyer, Mark D Huffman, Et Al.

2020-Current year OA Pubs

BACKGROUND: The Hypertension Treatment in Nigeria Program was implemented across 60 primary healthcare centers (PHCs) in Nigeria to improve hypertension treatment and control using the World Health Organization's HEARTS package. This study reports the program's implementation outcomes.

METHODS: The Hypertension Treatment in Nigeria Program used a type 2 hybrid interrupted time series design, and data were collected from January 2020 to December 2023. The RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework guided the evaluation, focusing on key metrics such as patients' and clinics' characteristics, prescription rate of fixed dose combination (FDC) drugs, medication availability, and retention.

RESULTS: Among 21,922 …

Molecular Basis Of Nfib-Mediated Regulation Of Oncogenic Transcription, Ci Zhu, Ding Xiao, Yueyu Wang, Hong Han, Chengxiao Qin, Shuang Liu, Xi Chen, Hejin Xiao, Xin Chen, Junfeng Shi, Juyu Tang, Jie Shen, He Song

2020-Current year OA Pubs

The Nuclear Factor I (NFI) family of transcription factors orchestrates key regulatory programs in development, differentiation, and metabolism, with dysregulation implicated in diverse pathological conditions, including cancer. Among the paralogs, NFIB has emerged as an oncogenic driver in multiple tumor types, yet the mechanisms through which it engages DNA and directs oncogenic transcriptional programs remain undefined. Here, using cancer cells with high NFIB expression, we demonstrate that NFIB promotes malignant phenotypes, as CRISPR-Cas9 knockout impairs proliferation, migration, and invasion. Transcriptomic profiling reveals that NFIB regulates a cancer-enriched gene network that includes FGFR3 and PDGFRB. Biophysical analyses show that NFIB, including …

Maternal Obesogenic Diet Exposure Regulates The Offspring Gut Liver Axis And Fibroinflammatory Liver Disease, Naresh Naik Ramavath, Oğuz Özler, Holly Hinrichs, Francisco R Victorino, Vung Lian, Monica Young, Tarin M Bigley, Michael D Thompson

2020-Current year OA Pubs

Maternal obesogenic diet exposure (MODE) promotes fibroinflammatory liver disease in offspring via vertical transfer of an altered microbiome. The mechanism for how an altered offspring microbiome increases susceptibility to liver disease is not clear. A critical early life event termed the 'weaning reaction' is dependent on the early microbiome and when altered, results in worse pathologic inflammation. MODE attenuates the weaning reaction promoting worse liver disease in mice in an early microbiome-dependent manner. Using our MODE model and cross-fostering approaches we assessed the effect of MODE on neonatal gut-liver axis development. MODE shifts the bile acid (BA) profile, expression of …

Deep Learning Reveals How Cells Pull, Buckle, And Navigate Fibrous Environments, Abinash Padhi, Arka Daw, Atharva Agashe, Medha Sawhney, Maahi M Talukder, Mehran M H Pour, Mohammad Jafari, Guy M Genin, Farid Alisafaei, Sohan Kale, Anuj Karpatne, Amrinder S Nain

2020-Current year OA Pubs

Cells in tissues navigate fibrous environments fundamentally differently than they do on flat substrates, but the establishment of cell forces in physiological fibrous settings remains poorly understood. Although factors such as the stiffness of the extracellular matrix (ECM) are known to drive behaviors, including cell motility on flat nonfibrous substrates, the interplay between fiber architecture and stiffness in fibrous ECM is not known. Here, we find that in fibrous environments, the directionality of mechanical forces overrides ECM stiffness as the primary regulator of contractility in migrating cells. Using an approach combining phase microscopy with deep learning to map forces in …

Mitochondrial Iron Transport Via Mfrn1 Is Required For Erythroid Cell Cycle Progression, Mark Perfetto, Aidan Danoff, Muhammad Ishfaq, Heidi Monroe, Aiden Mohideen, Meilin Chen, Jesus Tejero, Amber N Stratman, Satoshi Okawa, Yvette Y Yien

2020-Current year OA Pubs

Iron metabolism drives key erythropoietic processes, including hemoglobinization, survival, and proliferation. Here, we developed in vivo methods to interrogate how iron regulates erythropoiesis and report that mitochondrial iron transport via mitoferrin-1 (MFRN1) is essential for erythroid cell cycle progression. mfrn1 embryos had severely decreased erythroid cell number caused by cell cycle arrest at G2/M. They had enlarged nuclei, suggesting a mitotic defect. Iron supplementation rescued the cell cycle defect, implicating mitochondrial iron deficiency as its cause. In contrast, fpn1 mutants, anemic from systemic iron deficiency, had less severe decreases in erythroid mitochondrial iron than mfrn1 mutants and no proliferative defects. …

Prospective Sars-Cov-2 Additional Vaccination In Immunosuppressant-Treated Individuals With Autoimmune Diseases In A Randomized Controlled Trial, Meggan Mackay, Alfred Hj Kim, Et Al.

2020-Current year OA Pubs

BACKGROUND: Individuals with autoimmune diseases (AD) on immunosuppressants often have suboptimal responses to COVID-19 vaccine. We evaluated the efficacy and safety of additional COVID-19 vaccines in those treated with mycophenolate mofetil/mycophenolic acid (MMF/MPA), methotrexate (MTX), and B cell-depleting therapy (BCDT), including the impact of withholding MMF/MPA and MTX.

METHODS: In this open-label, multicenter, randomized trial, 22 participants taking MMF/MPA, 26 taking MTX, and 93 treated with BCDT who had suboptimal antibody responses to initial COVID-19 vaccines (2 doses of BNT162b2 or mRNA-1273 or 1 dose of AD26.COV2.S) received an additional homologous vaccine. Participants taking MMF/MPA and MTX were randomized (1:1) …

Cpx-351 Vs. Conventional Chemotherapy Cardiotoxicity In High-Risk Aml: A Post Hoc Phase Iii Trial Analysis, Joshua D Mitchell, Michael Pfeiffer, John Boehmer, John Gorcsan, Shunsuke Eguchi, Yoshiyuki Orihara, Nalina Dronamraju, Sonja Dhani, Stefan Faderl, Tara L Lin, Geoffrey L Uy, Jeffrey E Lancet, Jorge E Cortes

2020-Current year OA Pubs

BACKGROUND: CPX-351, a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, has demonstrated significantly improved overall survival in acute myeloid leukemia (AML) compared with 7 + 3, but its impact on cardiac function remains unclear. In a post hoc analysis of the pivotal clinical trial, we sought to determine the relative cardiotoxicity of CPX-351 vs. 7 + 3 in high-risk AML.

METHODS: We evaluated cardiotoxicity in 102 patients with AML (CPX-351, n = 57; 7 + 3, n = 45) who had normal baseline left ventricular ejection fraction (LVEF) ≥ 53% and at least one …

Cohort Profile: The Pharmacogenomics And Pharmacokinetics Study In Ghanaian Hiv Patients (Genopharm-Gh), Nicholas Ekow Thomford, Oksana Ryabinina, Joel Adu Twum, John Anyimadu, Samuel Badu Nyarko, Akwasi Anyanful, Martins Ekor, George Boateng Kyei

2020-Current year OA Pubs

BACKGROUND: The GenoPharm-GH project initiated in 2019, as a longitudinal, multi-site observational cohort study aimed at bridging gaps in understanding the influence of host genetics, pharmacokinetics and comorbidities on treatment outcome among persons living with HIV (PLWH) in Ghana.

METHODS: The study is ongoing prospective, longitudinal, multi-site cohort associated with diverse projects being conducted throughout health facilities across Ghana. So far 2044 persons living with HIV (PLWH) aged ≥ 8 years have been registered. These participants are on treatment with antiretroviral therapies (ART). Viral suppression, treatment adherence (self-reported and pill count), clinical data, genetic variations, coinfections, and comorbidities are being …

Single-Cell Transcriptomic Analysis Of Hpv-Related Multiphenotypic Sinonasal Carcinoma Uncovers Myb-Hpv Association, Avishai Wizel, Matthew D A Spence, Michael Mints, William Britton, Ogoegbunam Okolo, Victoria Yu, Isabel Cioffi, Salvatore Caruana, Scott H Troob, William C Faquin, Derrick T Lin, Itay Tirosh, Sidharth V Puram, Anuraag S Parikh, Yotam Drier

2020-Current year OA Pubs

Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC) is a rare tumor that morphologically resembles high-grade adenoid cystic carcinoma (ACC) but exhibits indolent clinical behavior. Both demonstrate MYB proto-oncogene upregulation, though HMSC lacks the MYB translocation characteristic of ACC. We performed single-cell RNA sequencing on an HMSC tumor and compared expression patterns with published ACC and oropharyngeal squamous cell carcinoma (OPSCC) datasets. Malignant HMSC cells clustered separately from ACC and lacked bicellular luminal and myoepithelial differentiation. A greater proportion of HMSC cells expressing HPV-related genes (HPVon) expressed MYB (83% vs. 62%, p = 0.022) and MYB targets (p = 6.4 × …

Multidomain Therapy For Alzheimer's Disease: A Scoping Review Of Cognitive Decline Trials, Jared C Roach, Cyrus A Raji, Et Al.

2020-Current year OA Pubs

BACKGROUND: Alzheimer’s disease (AD) leading to cognitive decline and dementia results from the interplay of multiple interacting dysfunctional biological systems. These systems can be categorized by domain, such as inflammation, cardiovascular health, proteostasis, or metabolism. Specific causes of AD differ between individuals, but each individual is likely to have causes stemming from multiple domains. Personalized multidomain therapy has been proposed as a standard of care for AD. OBJECTIVES: We sought to enumerate and describe prospective randomized controlled trials (RCTs) for multidomain interventions for AD, and to extract their inclusion criteria, trial design parameters (length, number of participants), and outcome measures. …

A Cluster-Randomized Controlled Trial Assessing The Effectiveness Of A Multifaceted Versus A Discrete Implementation Strategy On Fidelity To An Occupational Guideline For The Prevention Of Mental Health Problems At The Workplace: A Dual Perspective From Swedish Schools, Andreas Rödlund, Anna Toropova, Rebecca Lengnick-Hall, Byron J Powell, Liselotte Schäfer Elinder, Christina Björklund, Lydia Kwak

2020-Current year OA Pubs

BACKGROUND: Although the management of psychosocial risks in the work environment represents an evidence-based approach to the prevention of mental health problems, its implementation is limited, including in schools, and knowledge on how to support better implementation is scarce. This study compares the effectiveness of a multifaceted vs. a discrete implementation strategy on fidelity to an occupational guideline for the prevention of mental health problems. Dual perspectives were used to assess fidelity, an important aspect of the measurement agenda.

METHODS:  A cluster-randomized controlled trial was conducted among 55 schools in Sweden. A multifaceted strategy (educational meeting, implementation teams, ongoing training, …

Assessing The Usability Of A Novel Toolkit For Creating Visual Key Information Pages For Informed Consent For Research: Mixed Methods Usability Study, Eliana Charlotte Goldstein, Zoe Troubh, Krista E Cooksey, Molly Volkmar, Victor Catalan Gallegos, Kimberly A Kaphingst, Clara N Lee, Ashley J Housten, Jessica Mozersky, Mary C Politi

2020-Current year OA Pubs

BACKGROUND: Key information pages for informed consent require a concise summary of information to improve participant understanding but have not widely incorporated health literacy best practices.

OBJECTIVE: We previously developed a visual key information template to improve informed consent. In this study, we conducted usability testing of this customizable one-page key information template.

METHODS: We used the Designing for Accelerated Translation framework to plan for actionable, efficient usability testing. Participants (N=15) were asked to spend about 20 minutes using the visual key information template and engaging in a think-aloud protocol. They then responded to qualitative debrief questions about the template …

Mu-Glioma Post: A Comprehensive Dataset Of Automated Mr Multi-Sequence Segmentation And Clinical Features, Esmat Mahmoud, Jaime Gass, Yaseen Dhemesh, Josh Greaser, Karolina Pogorzelski, Edvin Isufi, Filip Garrett, Jonathan Thacker, Nourel Hoda Tahon, Jason Sinclair, Lester Layfield, Talissa Altes, Ayman Nada

2020-Current year OA Pubs

Gliomas represent a heterogenous group of primary brain tumors with overlapping imaging phenotypes. Treatment typically includes surgery and/or chemoradiation, however this varies based on the overall lesion and clinical presentation. This heterogeneity in both lesion characteristics and management strategies contributes to a lack of reliable findings when evaluating treatment outcomes with conventional MRI. The overlapping imaging features of radiation necrosis and tumor progression post-treatment can be particularly challenging for radiologists. We present a dataset of 203 glioma patients with 594 post-treatment timepoints of relevant clinical history and routine T1, T1 postcontrast, T2, and FLAIR weighted MR sequences. Preprocessing of the …

Modulation Of Dorsal Hippocampal Sk2 Channels Regulates Morphine-Enhanced Neuronal Oscillations And Morphine-Induced Contextual Memory Encoding And Retrieval, Khairunisa Mohamad Ibrahim, Dominika J Burek, Azra Zec, Olayinka Idowu, Will W Post, Alice Zheng, Basma Daham, Justin D Meyer, Sidney Williams, Nicolas Massaly, Jose A Morón

2020-Current year OA Pubs

Persistent maladaptive drug-context associations are a key component of relapse vulnerability and pose a major obstacle in treating opioid use disorder. Although the dorsal hippocampus (dHPC) is critical for contextual memory formation, the synaptic mechanisms by which opioids alter hippocampal circuits to sustain these associations remain unclear. We previously found that repeated context-paired morphine exposure impairs dHPC long-term potentiation (LTP) through enhanced activity of small-conductance calcium-activated potassium (SK2) channels. Here, we investigated the role of SK2 channels in morphine-context associative learning and memory by combining in vivo electrophysiology, molecular analyses, and behavioral pharmacology with the morphine-conditioned place preference (MorCPP) paradigm …

Design And Implementation Of A Drug Revolving Fund For Hypertension Treatment In Primary Care Setting Of The Federal Capital Territory, Nigeria, Grace Julcit Shedul, Erica L Jamro, Mark D Huffman, Et Al.

2020-Current year OA Pubs

BACKGROUND: Expanding treatment for hypertension requires ensuring access to affordable, high-quality blood pressure (BP) lowering medications. We describe the design, implementation and evaluation of a BP-lowering medication drug revolving fund (DRF) embedded in the Hypertension Treatment in Nigeria (HTN) Programme in 60 primary healthcare centres (PHCs) in the Federal Capital Territory, Nigeria.

METHODS: We used the exploration, preparation, implementation and sustainment framework to describe the DRF design and implementation and the reach, effectiveness, adoption, implementation and maintenance framework to report implementation outcomes. From June 2022 to December 2023, the DRF programme was implemented, and the data were collected from PHCs' …

Two Unrelated Pseudomonas Aeruginosa Phages Require The Exopolysaccharide Psl For Infection, Kristen Amyx-Sherer, Leila C Awasthi, Amanda Zheng, Anna Johannesman, Michele Leroux, Courtney Reichhardt

2020-Current year OA Pubs

Bacteria commonly protect themselves from a variety of threats by forming biofilms, which are communities of bacteria that are tightly packed together within an extracellular matrix. Biofilm formation has generally been thought to protect bacteria from phage infection. The opportunistic pathogen Pseudomonas aeruginosa produces biofilm matrices that can contain three distinct exopolysaccharides that contribute to the difficulty in treating infected patients. Here, we demonstrate that two diverse P. aeruginosa phages have evolved to exploit this biofilm matrix to access the bacterial cells by both binding to and degrading a major biofilm exopolysaccharide, Psl. We examined the effect of these phages …

Bladder Health And The Urogenital Microbiome In Community-Dwelling Adult Females, L Brubaker, D Mcdonald, S Putnam, C Brennan, C S Fok, C E Lewis, J L Lowder, M G Mueller, L M Rickey, E R Mueller, S J Song, K Rudser, R Knight, E S Lukacz, Plus Consortium

2020-Current year OA Pubs

UNLABELLED: Despite the established association with lower urinary tract symptoms, the relationship between a healthy bladder and the urogenital microbiome is unknown. This observational cohort study of 435 community-dwelling women examined bladder health and function using a validated instrument. Voided urine samples were self-collected, shipped to a repository, and underwent 16S rRNA amplicon sequencing. Two hundred seventy-four (56%) samples were retained following a limit-of-detection analysis for low biomass samples. A differential abundance analysis showed that

IMPORTANCE: There is increasing awareness that human microbiomes impact health and modulate certain health conditions. Recently, investigators developed a validated assessment of bladder health in …

Depth-Variant Deconvolution Applied To Widefield Microscopy For Rapid Large-Volume Tissue Imaging, Daniel D Lee, Kevin A Telfer, Mark A J Koenis, Yim K Lee, Kevin W Namink, Brian T Saunders, Heyun Lee, Hailey Kelley, Heather S Ruiz, Joseph P Gaut, Gwendalyn J Randolph, Bernd H Zinselmeyer

2020-Current year OA Pubs

Innovations in 3D tissue imaging have revolutionized research, but limitations stemming from lengthy protocols and equipment accessibility persist. Widefield microscopy is fast and accessible but often excluded from 3D imaging workflows due to its lack of optical sectioning. Here we combine tissue clearing with a commercial depth-variant deconvolution approach that we optimized for large-volume widefield imaging. By implementing prefiltering with z-brick splitting, we achieve subnuclear axial resolution in tissues to a depth of 500 µm in multi-tile scan images. We illustrate the utility of this method in a model of ileitis and to gain a 3D perspective in thick brain …

Strategies To Improve Healthcare Team Communication Structure And Quality In Resource-Variable Childhood Cancer Hospitals (Teamtalk): A Study Protocol, Asya Agulnik, Dylan E Graetz, Bobbi J Carothers, Jocelyn Rivera, Erin Abu-Rish Blakeney, Samantha Hayes, Veronica L Chaitan, Leopoldo Cabassa, Charles W Goss, Douglas A Luke, Sara Malone

2020-Current year OA Pubs

BACKGROUND: Healthcare team communication is essential to high-quality childhood cancer care, especially during high-acuity events such as clinical deterioration and in resource-variable settings, where supportive interventions to resolve deterioration are less available. Communication quality has traditionally been understudied in these settings, and there is a notable lack of communication interventions that are appropriate and feasible in settings across resource levels. We propose addressing this challenge in this study protocol, which will co-develop and pilot a multi-level intervention to improve communication and outcomes for children receiving cancer treatment.

METHODS/DESIGN: This study leverages systems and implementation science methodologies to evaluate and improve …

High-Sensitivity Plasma Proteomics Reveals Disease-Specific Signatures And Predictive Biomarkers Of Alzheimer's Disease Phenotypes In A Large Mixed-Dementia Cohort, Katherine Gong, Jigyasha Timsina, Muhammad Ali, Yike Chen, Menghan Liu, Ciyang Wang, Cyril Pottier, Geoffrey K Feld, Gyujin Heo, Tammie L S Benzinger, Cyrus A Raji, Beau Ances, Brian A Gordon, Julie K Wisch, Suzanne E Schindler, John C Morris, David M Holtzman, Laura Ibanez, Carlos Cruchaga

2020-Current year OA Pubs

Novel plasma assays enabled accurate blood-based biomarkers for neurodegenerative diseases with minimally invasive options for clinical use. Large-scale studies encompassing multiple neurodegenerative diseases using novel multiplex platforms are essential to uncover disease-specific biomarkers and pathways. We generated and analyzed plasma biomarker data using the NULISAseq™ CNS Panel from 3,232 participants with Alzheimer disease (AD), Dementia with Lewy bodies (DLB), Frontotemporal dementia (FTD), Parkinson disease (PD) and cognitively unimpaired individuals, from the Charles F. and Joanne Knight Alzheimer Disease Research Center. We identified proteins associated with disease status and AD-related phenotypes (Clinical Dementia Rating®, CSF Aβ42/Aβ40, Amyloid-PET, and Tau-PET). These proteins …

Dietary Sources Of Sodium Intake In Nigerian Adults: A Population-Based Cross-Sectional Study, Clementina E Okoro, Erica L Jamro, Guhan Iyer, Mark D Huffman, Et Al.

2020-Current year OA Pubs

Nigeria seeks to address the growing burden of hypertension and related diseases by reducing excessive dietary sodium through national dietary policymaking. This study aims to describe the levels and sources of dietary sodium intake among Nigerian adults to inform these policies. From June 2023 to July 2023, adults aged 18 to 69 years old were recruited from the Federal Capital Territory, Kano, and Ogun states to participate in a population-based, cross-sectional demographic health survey. Data were also collected to assess levels and dietary sources of sodium through four 24-h dietary recalls by trained study personnel. The primary analyses included the …

Developing A Genetic Return Of Results Service Core, Jennifer A Mckenzie, Erin Mcroy, Kevin M Bowling, Jorge Luis Granadillo De Luque, Jessica Mozersky, Erin Linnenbringer, Dustin Baldridge, Jonathan W Heusel, Julie A Neidich, Amanda F Cashen, Laura J Bierut, Sarah M Hartz, Christina A Gurnett

2020-Current year OA Pubs

Research participants should be informed of genetic test results that could impact their health, particularly when they have expressed interest in receiving such information. Furthermore, the return of genetic test results is essential to improve trust, transparency, and health equity. However, investigators often encounter barriers in returning genetic test results to research participants. We examined genomic research at a large, research-intensive medical school and found less than 6% of protocols included plans to return results to participants. This study describes our development of protocols for returning primary and secondary genetic test results and implementation of a Genomic Return of Results …

Ptbp1 Variants Displaying Altered Nucleocytoplasmic Distribution Are Responsible For A Neurodevelopmental Disorder With Skeletal Dysplasia, Aymeric Masson, Catherine Gooch, Et Al.

2020-Current year OA Pubs

Polypyrimidine tract-binding protein 1 (PTBP1) is a heterogeneous nuclear ribonucleoprotein primarily known for its alternative splicing activity. It shuttles between the nucleus and cytoplasm via partially overlapping N-terminal nuclear localization (NLS) and export (NES) signals. Despite its fundamental role in cell growth and differentiation, its involvement in human disease remains poorly understood. We identified 27 individuals from 25 families harboring de novo or inherited pathogenic variants - predominantly start-loss (89%) and, to a lesser extent, missense (11%) - affecting NES/NLS motifs. Affected individuals presented with a syndromic neurodevelopmental disorder and variable skeletal dysplasia with disproportionate short stature with short limbs. …

Intersectional Stigma And Resilience In The Uptake Of Cervical Cancer Prevention Services In Nigeria: A Qualitative Study, Agatha Eileen Wapmuk, Titilola Abike Gbaja-Biamila, Ekenechukwu Kokelu, Juliet Iwelunmor, Et Al.

2020-Current year OA Pubs

BACKGROUND: Cervical cancer is one of the leading causes of death among women in Africa, but stigma often delays cervical cancer prevention. We explore the perceptions, enablers and nurturers through the lens of intersectional stigma in the uptake of cervical cancer prevention services in Nigeria.

METHOD: Indepth interviews and focus group discussions were conducted among women aged 30-65 years and girls aged 9-26 years in Lagos, Nigeria. Data were analysed thematically. Using the relationships and expectation domain of the PEN-3 cultural model, we identified perceptions, enablers and nurturers related to the uptake of primary and secondary cervical cancer prevention services …

The Effects Of Marital Status, Partner Drinking, And Sex Differences On The Likelihood Of Remission From Alcohol Use Disorder, Christina Garasky, Alexis Duncan, Fanghong Dong, Jared Balbona, Andrey Anokhin, Emma Johnson, Arpana Agrawal, Kathleen Bucholz, Vivia Mccutcheon, Et Al.

2020-Current year OA Pubs

OBJECTIVE: Marriage is associated with improved health and alcohol outcomes, yet prior research has often combined diverse non-marital relationships, obscuring whether benefits are unique to marriage or a result of strong interpersonal relationships. This study examines whether marriage, compared to cohabitation, exclusive dating, or being single, is associated with alcohol use disorder (AUD) remission and whether this varies by sex and partner drinking.

METHOD: Participants were adults from the Collaborative Study on the Genetics of Alcoholism Lifespan Study (n = 1494; 54.4% female) who met criteria for lifetime DSM-5 AUD. Multivariate logistic regression models examined the association between marital status …

Generation And Characterization Of A Knockout Mouse Of An Enhancer Of Ebf3, Emily Cordova Hurtado, Janine M Wotton, Alexander Gulka, Crystal Burke, Jeffrey K Ng, Ibrahim Bah, Juana Manuel, Hillary Heins, Stephen A Murray, David U Gorkin, Jacqueline K White, Kevin A Peterson, Tychele N Turner

2020-Current year OA Pubs

Genomic studies of neurodevelopmental disorders (NDDs) have identified several relevant genomic variants. EBF3 is a gene with an excess of protein-coding de novo variants and underlies Hypotonia, Ataxia, and Delayed Development Syndrome. We previously identified noncoding de novo variants in an enhancer of EBF3 and further found enrichment of deletions of this enhancer in NDDs. In this study, we generated a novel mouse line that deletes the highly conserved, orthologous mouse region within the Rr169617 regulatory region, and characterized the molecular and phenotypic aspects of this mouse model. We found a deviation from Mendelian expectation (P=0.02) with significant depletion of …

Validation Of A Two-Item Short Form Of The Perceived Health Competence Scale, Devika Nair, Jacquelyn S Pennings, Hayden B Bosworth, Kenneth E Freedland, Sunil Kripalani, Elisa J Gordon, Gurjeet S Birdee, Justin M Bachmann

2020-Current year OA Pubs

BACKGROUND: Perceived health competence is a construct encompassing individuals’ confidence in managing their health and health-related behaviors. The 8-item Perceived Health Competence Scale (PHCS-8), developed to measure this construct, has established psychometric properties including test-retest reliability and predictive validity for health behaviors and clinical outcomes. We aimed to validate the 2-item Perceived Health Competence Scale (PHCS-2), an abbreviated version of the PHCS-8, for use in clinical and research settings where respondent burden is a primary concern. METHODOLOGY: We conducted a psychometric validation study using pooled data from 482 participants across two cohort studies conducted in an integrative medicine clinic. Participants …

Mta-Cooperative Prmt5 Inhibitors Are Efficacious In Mtap-Deleted Malignant Peripheral Nerve Sheath Tumor Models, Xiaochun Zhang, Dana C Borcherding, Yang Lyu, Guangfeng Wang, Kevin He, Gorkem Oztosun, Ishita Sachdeva, Liuzhan Yang, Kuangying Yang, Angela C Hirbe, Et Al.

2020-Current year OA Pubs

PURPOSE: Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with poor prognosis. The enzyme methylthioadenosine phosphorylase (MTAP) is lost in ∼25% to 50% of MPNSTs, which is associated with loss of the tumor suppressor gene CDKN2A. Inhibition of PRMT5 was found to be synthetically lethal in cells with MTAP loss due to accumulation of the substrate methylthioadenosine (MTA), an endogenous PRMT5 inhibitor. TNG908 and TNG462 are clinical-stage MTA-cooperative PRMT5 inhibitors that demonstrate selectivity for MTAP-deleted (null) cells over MTAP-proficient [wild-type (WT)] cells. Both compounds drive durable tumor regressions in various cancer xenograft models with MTAP loss.

EXPERIMENTAL DESIGN: …

Lair1 Prevents Excess Inflammatory Tissue Damage In Staphylococcus Aureus Skin Infection And Cutaneous T-Cell Lymphoma, Hannah K. Dorando, Evan C. Mutic, Kelly L. Tomaszewski, Yulia Korshunova, Ling Tian, Mellisa K. Stefanov, Chaz C. Quinn, Deborah J. Veis, Juliane Bubeck Wardenburg, Amy C. Musiek, Neha Mehta-Shah, Jacqueline E. Payton

2020-Current year OA Pubs

Patients with cutaneous T cell lymphoma (CTCL) experience high morbidity and mortality due to S. aureus skin infections and sepsis, but the underlying mechanisms remain unclear. We have previously identified high levels of LAIR2, a decoy protein for the inhibitory receptor LAIR1, in advanced CTCL. Mice lack a LAIR2 homolog, so we used Lair1 knock-out (KO) mice to model LAIR2 overexpression. In a model of S. aureus skin infection, Lair1 KO mice had significantly larger abscesses and areas of dermonecrosis compared to WT despite similar bacterial burdens. Lair1 KO exhibited a pattern of increased inflammatory responses in infection and sterile …

Targeting Tomm40 And Tomm22 To Rescue Statin-Impaired Mitochondrial Function, Dynamics, And Mitophagy In Skeletal Myotubes, Neil V Yang, Sean Rogers, Rachel Guerra, Justin Y Chao, David J Pagliarini, Elizabeth Theusch, Ronald M Krauss

2020-Current year OA Pubs

Statins are the drugs most commonly used for lowering plasma low-density lipoprotein (LDL) cholesterol levels and reducing cardiovascular disease risk. Although generally well-tolerated, statins can induce myopathy, a major cause of non-adherence to treatment. Impaired mitochondrial function has been implicated in the development of statin-induced myopathy, but the underlying mechanism remains unclear. We have shown that simvastatin downregulates the transcription of